WO2020242765A1 - Peptides modifiés à l'échelle mésométrique et procédés de sélection - Google Patents
Peptides modifiés à l'échelle mésométrique et procédés de sélection Download PDFInfo
- Publication number
- WO2020242765A1 WO2020242765A1 PCT/US2020/032715 US2020032715W WO2020242765A1 WO 2020242765 A1 WO2020242765 A1 WO 2020242765A1 US 2020032715 W US2020032715 W US 2020032715W WO 2020242765 A1 WO2020242765 A1 WO 2020242765A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- constraints
- derived
- reference target
- engineered peptide
- peptide
- Prior art date
Links
- 108090000765 processed proteins & peptides Proteins 0.000 title claims abstract description 461
- 238000000034 method Methods 0.000 title claims abstract description 199
- 102000004196 processed proteins & peptides Human genes 0.000 title claims abstract description 143
- 230000027455 binding Effects 0.000 claims abstract description 104
- 238000012216 screening Methods 0.000 claims abstract description 22
- 150000001413 amino acids Chemical class 0.000 claims description 182
- 125000004429 atom Chemical group 0.000 claims description 131
- 230000008827 biological function Effects 0.000 claims description 74
- 230000008512 biological response Effects 0.000 claims description 70
- 108090000623 proteins and genes Proteins 0.000 claims description 63
- 102000004169 proteins and genes Human genes 0.000 claims description 51
- 230000037361 pathway Effects 0.000 claims description 48
- 239000000126 substance Substances 0.000 claims description 43
- 230000004048 modification Effects 0.000 claims description 39
- 238000012986 modification Methods 0.000 claims description 39
- 230000028327 secretion Effects 0.000 claims description 36
- 229920001184 polypeptide Polymers 0.000 claims description 35
- 238000002965 ELISA Methods 0.000 claims description 32
- 230000000694 effects Effects 0.000 claims description 30
- 229910052739 hydrogen Inorganic materials 0.000 claims description 28
- 239000001257 hydrogen Substances 0.000 claims description 28
- 210000004027 cell Anatomy 0.000 claims description 27
- 239000000203 mixture Substances 0.000 claims description 27
- 230000004044 response Effects 0.000 claims description 27
- 238000003556 assay Methods 0.000 claims description 26
- 230000003993 interaction Effects 0.000 claims description 25
- 238000000329 molecular dynamics simulation Methods 0.000 claims description 22
- 238000004458 analytical method Methods 0.000 claims description 19
- 230000008236 biological pathway Effects 0.000 claims description 18
- 238000001514 detection method Methods 0.000 claims description 17
- 230000014509 gene expression Effects 0.000 claims description 16
- 238000010801 machine learning Methods 0.000 claims description 16
- 239000002904 solvent Substances 0.000 claims description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 claims description 12
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 claims description 12
- 108091000080 Phosphotransferase Proteins 0.000 claims description 12
- 230000003013 cytotoxicity Effects 0.000 claims description 12
- 231100000135 cytotoxicity Toxicity 0.000 claims description 12
- 102000020233 phosphotransferase Human genes 0.000 claims description 12
- 238000004088 simulation Methods 0.000 claims description 12
- 102000004310 Ion Channels Human genes 0.000 claims description 11
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 claims description 11
- 230000006870 function Effects 0.000 claims description 11
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 claims description 11
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 10
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 10
- 230000005847 immunogenicity Effects 0.000 claims description 10
- 102000000588 Interleukin-2 Human genes 0.000 claims description 9
- 108010002350 Interleukin-2 Proteins 0.000 claims description 9
- 238000005094 computer simulation Methods 0.000 claims description 9
- 230000002163 immunogen Effects 0.000 claims description 9
- 238000007385 chemical modification Methods 0.000 claims description 8
- 230000002209 hydrophobic effect Effects 0.000 claims description 8
- 230000035772 mutation Effects 0.000 claims description 8
- 238000012549 training Methods 0.000 claims description 8
- 102000004127 Cytokines Human genes 0.000 claims description 6
- 108090000695 Cytokines Proteins 0.000 claims description 6
- 108010033040 Histones Proteins 0.000 claims description 6
- 102000008070 Interferon-gamma Human genes 0.000 claims description 6
- 108010074328 Interferon-gamma Proteins 0.000 claims description 6
- 102000018697 Membrane Proteins Human genes 0.000 claims description 6
- 108010052285 Membrane Proteins Proteins 0.000 claims description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 6
- 102000004887 Transforming Growth Factor beta Human genes 0.000 claims description 6
- 108090001012 Transforming Growth Factor beta Proteins 0.000 claims description 6
- 230000021736 acetylation Effects 0.000 claims description 6
- 238000006640 acetylation reaction Methods 0.000 claims description 6
- 230000004913 activation Effects 0.000 claims description 6
- 230000008484 agonism Effects 0.000 claims description 6
- 125000000539 amino acid group Chemical group 0.000 claims description 6
- 230000008485 antagonism Effects 0.000 claims description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 6
- 210000003719 b-lymphocyte Anatomy 0.000 claims description 6
- 230000015572 biosynthetic process Effects 0.000 claims description 6
- 230000006652 catabolic pathway Effects 0.000 claims description 6
- 230000030833 cell death Effects 0.000 claims description 6
- 230000022534 cell killing Effects 0.000 claims description 6
- 230000004663 cell proliferation Effects 0.000 claims description 6
- 230000035605 chemotaxis Effects 0.000 claims description 6
- 230000000295 complement effect Effects 0.000 claims description 6
- 230000001973 epigenetic effect Effects 0.000 claims description 6
- 230000004049 epigenetic modification Effects 0.000 claims description 6
- 230000004907 flux Effects 0.000 claims description 6
- 230000002068 genetic effect Effects 0.000 claims description 6
- 239000003102 growth factor Substances 0.000 claims description 6
- 229940088597 hormone Drugs 0.000 claims description 6
- 239000005556 hormone Substances 0.000 claims description 6
- 210000002865 immune cell Anatomy 0.000 claims description 6
- 230000008595 infiltration Effects 0.000 claims description 6
- 238000001764 infiltration Methods 0.000 claims description 6
- 230000002757 inflammatory effect Effects 0.000 claims description 6
- 230000005764 inhibitory process Effects 0.000 claims description 6
- 102000006495 integrins Human genes 0.000 claims description 6
- 108010044426 integrins Proteins 0.000 claims description 6
- 229960003130 interferon gamma Drugs 0.000 claims description 6
- 108020004999 messenger RNA Proteins 0.000 claims description 6
- 230000002503 metabolic effect Effects 0.000 claims description 6
- 230000037353 metabolic pathway Effects 0.000 claims description 6
- 230000011987 methylation Effects 0.000 claims description 6
- 238000007069 methylation reaction Methods 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 230000014207 opsonization Effects 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 239000001301 oxygen Substances 0.000 claims description 6
- 230000035699 permeability Effects 0.000 claims description 6
- 230000004481 post-translational protein modification Effects 0.000 claims description 6
- 230000012846 protein folding Effects 0.000 claims description 6
- 230000002797 proteolythic effect Effects 0.000 claims description 6
- 230000007111 proteostasis Effects 0.000 claims description 6
- 230000019491 signal transduction Effects 0.000 claims description 6
- 230000011664 signaling Effects 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- 239000011593 sulfur Substances 0.000 claims description 6
- 210000000225 synapse Anatomy 0.000 claims description 6
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 claims description 6
- 238000013518 transcription Methods 0.000 claims description 6
- 230000035897 transcription Effects 0.000 claims description 6
- 238000013519 translation Methods 0.000 claims description 6
- 108700028369 Alleles Proteins 0.000 claims description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 5
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 5
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 5
- ZOKXTWBITQBERF-UHFFFAOYSA-N Molybdenum Chemical compound [Mo] ZOKXTWBITQBERF-UHFFFAOYSA-N 0.000 claims description 5
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 5
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 5
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 210000000170 cell membrane Anatomy 0.000 claims description 5
- 229910052802 copper Inorganic materials 0.000 claims description 5
- 239000010949 copper Substances 0.000 claims description 5
- 238000005421 electrostatic potential Methods 0.000 claims description 5
- 230000002255 enzymatic effect Effects 0.000 claims description 5
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 5
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 5
- 238000000099 in vitro assay Methods 0.000 claims description 5
- 238000005462 in vivo assay Methods 0.000 claims description 5
- 229910052742 iron Inorganic materials 0.000 claims description 5
- 229910052749 magnesium Inorganic materials 0.000 claims description 5
- 239000011777 magnesium Substances 0.000 claims description 5
- 230000014759 maintenance of location Effects 0.000 claims description 5
- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 claims description 5
- 229910052750 molybdenum Inorganic materials 0.000 claims description 5
- 239000011733 molybdenum Substances 0.000 claims description 5
- 229910052759 nickel Inorganic materials 0.000 claims description 5
- 229910052698 phosphorus Inorganic materials 0.000 claims description 5
- 239000011574 phosphorus Substances 0.000 claims description 5
- 239000011591 potassium Substances 0.000 claims description 5
- 229910052700 potassium Inorganic materials 0.000 claims description 5
- 238000012545 processing Methods 0.000 claims description 5
- 230000004853 protein function Effects 0.000 claims description 5
- 230000009257 reactivity Effects 0.000 claims description 5
- 229910052708 sodium Inorganic materials 0.000 claims description 5
- 239000011734 sodium Substances 0.000 claims description 5
- 238000007614 solvation Methods 0.000 claims description 5
- 230000003746 surface roughness Effects 0.000 claims description 5
- 239000011701 zinc Substances 0.000 claims description 5
- 229910052725 zinc Inorganic materials 0.000 claims description 5
- 210000001744 T-lymphocyte Anatomy 0.000 claims description 4
- 108010067902 Peptide Library Proteins 0.000 claims description 3
- 238000010822 cell death assay Methods 0.000 claims description 3
- 238000001516 cell proliferation assay Methods 0.000 claims description 3
- 230000015861 cell surface binding Effects 0.000 claims description 3
- 230000009144 enzymatic modification Effects 0.000 claims description 3
- 238000001952 enzyme assay Methods 0.000 claims description 3
- 238000003364 immunohistochemistry Methods 0.000 claims description 3
- 230000009145 protein modification Effects 0.000 claims description 3
- 238000001262 western blot Methods 0.000 claims description 3
- 238000000342 Monte Carlo simulation Methods 0.000 claims description 2
- 238000012512 characterization method Methods 0.000 claims description 2
- 239000011159 matrix material Substances 0.000 description 55
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 48
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 45
- 238000000338 in vitro Methods 0.000 description 39
- 238000004091 panning Methods 0.000 description 38
- 239000013598 vector Substances 0.000 description 27
- 230000000903 blocking effect Effects 0.000 description 25
- 125000003275 alpha amino acid group Chemical group 0.000 description 24
- 230000033001 locomotion Effects 0.000 description 18
- 102000008096 B7-H1 Antigen Human genes 0.000 description 15
- 108010074708 B7-H1 Antigen Proteins 0.000 description 15
- 210000004602 germ cell Anatomy 0.000 description 14
- 229960000397 bevacizumab Drugs 0.000 description 12
- 238000013461 design Methods 0.000 description 11
- 238000011545 laboratory measurement Methods 0.000 description 11
- 229950002916 avelumab Drugs 0.000 description 10
- 229950009791 durvalumab Drugs 0.000 description 9
- 238000013459 approach Methods 0.000 description 8
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 7
- 238000010586 diagram Methods 0.000 description 7
- 238000012900 molecular simulation Methods 0.000 description 7
- 238000000126 in silico method Methods 0.000 description 6
- 238000007481 next generation sequencing Methods 0.000 description 6
- 230000001225 therapeutic effect Effects 0.000 description 6
- 102100035360 Cerebellar degeneration-related antigen 1 Human genes 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- 108010090804 Streptavidin Proteins 0.000 description 5
- 239000000427 antigen Substances 0.000 description 5
- 108091007433 antigens Proteins 0.000 description 5
- 102000036639 antigens Human genes 0.000 description 5
- 238000005070 sampling Methods 0.000 description 5
- 229960002685 biotin Drugs 0.000 description 4
- 235000020958 biotin Nutrition 0.000 description 4
- 239000011616 biotin Substances 0.000 description 4
- 238000010276 construction Methods 0.000 description 4
- 238000000513 principal component analysis Methods 0.000 description 4
- 230000000717 retained effect Effects 0.000 description 4
- 239000000523 sample Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 102100023990 60S ribosomal protein L17 Human genes 0.000 description 3
- 102100031650 C-X-C chemokine receptor type 4 Human genes 0.000 description 3
- 241000282693 Cercopithecidae Species 0.000 description 3
- 101000922348 Homo sapiens C-X-C chemokine receptor type 4 Proteins 0.000 description 3
- 101001057504 Homo sapiens Interferon-stimulated gene 20 kDa protein Proteins 0.000 description 3
- 101001055144 Homo sapiens Interleukin-2 receptor subunit alpha Proteins 0.000 description 3
- 102100026878 Interleukin-2 receptor subunit alpha Human genes 0.000 description 3
- 102000034655 MIF Human genes 0.000 description 3
- 108060004872 MIF Proteins 0.000 description 3
- 101710089372 Programmed cell death protein 1 Proteins 0.000 description 3
- 239000012491 analyte Substances 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 238000010187 selection method Methods 0.000 description 3
- 238000012163 sequencing technique Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 102000000844 Cell Surface Receptors Human genes 0.000 description 2
- 108010001857 Cell Surface Receptors Proteins 0.000 description 2
- 238000012313 Kruskal-Wallis test Methods 0.000 description 2
- 241000282567 Macaca fascicularis Species 0.000 description 2
- 230000006399 behavior Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000003066 decision tree Methods 0.000 description 2
- 239000013604 expression vector Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 2
- 230000003053 immunization Effects 0.000 description 2
- 238000007480 sanger sequencing Methods 0.000 description 2
- 108091006024 signal transducing proteins Proteins 0.000 description 2
- 102000034285 signal transducing proteins Human genes 0.000 description 2
- 230000000087 stabilizing effect Effects 0.000 description 2
- 230000003068 static effect Effects 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 238000012706 support-vector machine Methods 0.000 description 2
- 102000035160 transmembrane proteins Human genes 0.000 description 2
- 108091005703 transmembrane proteins Proteins 0.000 description 2
- 108090001008 Avidin Proteins 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- 238000007399 DNA isolation Methods 0.000 description 1
- 238000012286 ELISA Assay Methods 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 241000282553 Macaca Species 0.000 description 1
- 241000282560 Macaca mulatta Species 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- BAQMYDQNMFBZNA-UHFFFAOYSA-N N-biotinyl-L-lysine Natural products N1C(=O)NC2C(CCCCC(=O)NCCCCC(N)C(O)=O)SCC21 BAQMYDQNMFBZNA-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- BAQMYDQNMFBZNA-MNXVOIDGSA-N biocytin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)NCCCC[C@H](N)C(O)=O)SC[C@@H]21 BAQMYDQNMFBZNA-MNXVOIDGSA-N 0.000 description 1
- 238000004422 calculation algorithm Methods 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 230000009260 cross reactivity Effects 0.000 description 1
- 238000009795 derivation Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 102000034287 fluorescent proteins Human genes 0.000 description 1
- 108091006047 fluorescent proteins Proteins 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 210000004408 hybridoma Anatomy 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 238000009434 installation Methods 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 238000002703 mutagenesis Methods 0.000 description 1
- 231100000350 mutagenesis Toxicity 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 238000007637 random forest analysis Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000002864 sequence alignment Methods 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000000528 statistical test Methods 0.000 description 1
- 238000005309 stochastic process Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
Classifications
-
- G—PHYSICS
- G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
- G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
- G16B40/00—ICT specially adapted for biostatistics; ICT specially adapted for bioinformatics-related machine learning or data mining, e.g. knowledge discovery or pattern finding
- G16B40/20—Supervised data analysis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/001—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof by chemical synthesis
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6803—General methods of protein analysis not limited to specific proteins or families of proteins
- G01N33/6845—Methods of identifying protein-protein interactions in protein mixtures
-
- G—PHYSICS
- G06—COMPUTING; CALCULATING OR COUNTING
- G06N—COMPUTING ARRANGEMENTS BASED ON SPECIFIC COMPUTATIONAL MODELS
- G06N20/00—Machine learning
-
- G—PHYSICS
- G06—COMPUTING; CALCULATING OR COUNTING
- G06N—COMPUTING ARRANGEMENTS BASED ON SPECIFIC COMPUTATIONAL MODELS
- G06N20/00—Machine learning
- G06N20/10—Machine learning using kernel methods, e.g. support vector machines [SVM]
-
- G—PHYSICS
- G06—COMPUTING; CALCULATING OR COUNTING
- G06N—COMPUTING ARRANGEMENTS BASED ON SPECIFIC COMPUTATIONAL MODELS
- G06N20/00—Machine learning
- G06N20/20—Ensemble learning
-
- G—PHYSICS
- G06—COMPUTING; CALCULATING OR COUNTING
- G06N—COMPUTING ARRANGEMENTS BASED ON SPECIFIC COMPUTATIONAL MODELS
- G06N5/00—Computing arrangements using knowledge-based models
- G06N5/01—Dynamic search techniques; Heuristics; Dynamic trees; Branch-and-bound
-
- G—PHYSICS
- G06—COMPUTING; CALCULATING OR COUNTING
- G06N—COMPUTING ARRANGEMENTS BASED ON SPECIFIC COMPUTATIONAL MODELS
- G06N5/00—Computing arrangements using knowledge-based models
- G06N5/04—Inference or reasoning models
-
- G—PHYSICS
- G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
- G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
- G16B15/00—ICT specially adapted for analysing two-dimensional or three-dimensional molecular structures, e.g. structural or functional relations or structure alignment
- G16B15/20—Protein or domain folding
-
- G—PHYSICS
- G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
- G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
- G16B5/00—ICT specially adapted for modelling or simulations in systems biology, e.g. gene-regulatory networks, protein interaction networks or metabolic networks
-
- G—PHYSICS
- G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
- G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
- G16B5/00—ICT specially adapted for modelling or simulations in systems biology, e.g. gene-regulatory networks, protein interaction networks or metabolic networks
- G16B5/30—Dynamic-time models
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/10—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using coupling agents
-
- G—PHYSICS
- G06—COMPUTING; CALCULATING OR COUNTING
- G06N—COMPUTING ARRANGEMENTS BASED ON SPECIFIC COMPUTATIONAL MODELS
- G06N3/00—Computing arrangements based on biological models
- G06N3/02—Neural networks
- G06N3/04—Architecture, e.g. interconnection topology
- G06N3/044—Recurrent networks, e.g. Hopfield networks
-
- G—PHYSICS
- G06—COMPUTING; CALCULATING OR COUNTING
- G06N—COMPUTING ARRANGEMENTS BASED ON SPECIFIC COMPUTATIONAL MODELS
- G06N3/00—Computing arrangements based on biological models
- G06N3/02—Neural networks
- G06N3/04—Architecture, e.g. interconnection topology
- G06N3/045—Combinations of networks
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A90/00—Technologies having an indirect contribution to adaptation to climate change
- Y02A90/10—Information and communication technologies [ICT] supporting adaptation to climate change, e.g. for weather forecasting or climate simulation
Landscapes
- Engineering & Computer Science (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Physics & Mathematics (AREA)
- Theoretical Computer Science (AREA)
- Chemical & Material Sciences (AREA)
- Molecular Biology (AREA)
- Software Systems (AREA)
- Data Mining & Analysis (AREA)
- General Health & Medical Sciences (AREA)
- Biophysics (AREA)
- General Physics & Mathematics (AREA)
- Medical Informatics (AREA)
- Artificial Intelligence (AREA)
- Evolutionary Computation (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Computing Systems (AREA)
- Mathematical Physics (AREA)
- General Engineering & Computer Science (AREA)
- Bioinformatics & Computational Biology (AREA)
- Biotechnology (AREA)
- Organic Chemistry (AREA)
- Computer Vision & Pattern Recognition (AREA)
- Spectroscopy & Molecular Physics (AREA)
- Medicinal Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biochemistry (AREA)
- Biomedical Technology (AREA)
- Evolutionary Biology (AREA)
- Urology & Nephrology (AREA)
- Hematology (AREA)
- Immunology (AREA)
- Computational Linguistics (AREA)
- Genetics & Genomics (AREA)
- Gastroenterology & Hepatology (AREA)
- Physiology (AREA)
- Analytical Chemistry (AREA)
- Cell Biology (AREA)
- Food Science & Technology (AREA)
- Pathology (AREA)
Abstract
L'invention concerne des peptides modifiés qui comprennent une combinaison de contraintes topologiques associées à l'espace, au moins une contrainte étant dérivée d'une cible de référence, et des procédés de sélection desdits peptides modifiés. L'invention concerne en outre des procédés d'utilisation des peptides modifiés, comprenant en tant que molécules de sélection positive et/ou négative dans des procédés de criblage une bibliothèque de molécules de liaison.
Priority Applications (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA3142227A CA3142227A1 (fr) | 2019-05-31 | 2020-05-13 | Peptides modifies a l'echelle mesometrique et procedes de selection |
| EP20813167.2A EP3977117A4 (fr) | 2019-05-31 | 2020-05-13 | Peptides modifiés à l'échelle mésométrique et procédés de sélection |
| CN202080050892.XA CN114585918A (zh) | 2019-05-31 | 2020-05-13 | 中尺度工程化肽和选择方法 |
| JP2021570755A JP2022535511A (ja) | 2019-05-31 | 2020-05-13 | メソスケール操作されたペプチドおよび選択方法 |
| KR1020217043265A KR20220041784A (ko) | 2019-05-31 | 2020-05-13 | 메소 스케일 조작된 펩티드 및 선택 방법 |
| US17/537,215 US20220081472A1 (en) | 2019-05-31 | 2021-11-29 | Meso-scale engineered peptides and methods of selecting |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201962855767P | 2019-05-31 | 2019-05-31 | |
| US62/855,767 | 2019-05-31 |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US17/537,215 Continuation US20220081472A1 (en) | 2019-05-31 | 2021-11-29 | Meso-scale engineered peptides and methods of selecting |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2020242765A1 true WO2020242765A1 (fr) | 2020-12-03 |
Family
ID=73553528
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US2020/032724 WO2020242766A1 (fr) | 2019-05-31 | 2020-05-13 | Appareil à base d'apprentissage automatique pour la modification de peptides à l'échelle méso et procédés et système pour celui-ci |
| PCT/US2020/032715 WO2020242765A1 (fr) | 2019-05-31 | 2020-05-13 | Peptides modifiés à l'échelle mésométrique et procédés de sélection |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US2020/032724 WO2020242766A1 (fr) | 2019-05-31 | 2020-05-13 | Appareil à base d'apprentissage automatique pour la modification de peptides à l'échelle méso et procédés et système pour celui-ci |
Country Status (7)
| Country | Link |
|---|---|
| US (3) | US11545238B2 (fr) |
| EP (2) | EP3976083A4 (fr) |
| JP (2) | JP2022535511A (fr) |
| KR (2) | KR20220041784A (fr) |
| CN (2) | CN114585918A (fr) |
| CA (2) | CA3142339A1 (fr) |
| WO (2) | WO2020242766A1 (fr) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115512763A (zh) * | 2022-09-06 | 2022-12-23 | 北京百度网讯科技有限公司 | 多肽序列的生成方法、多肽生成模型的训练方法和装置 |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117980995A (zh) * | 2021-05-21 | 2024-05-03 | 蛋白胨有限公司 | 多肽结构的时空确定 |
| CN114065620B (zh) * | 2021-11-11 | 2022-06-03 | 四川大学 | 基于像素图表征和cnn的可解释性分子动力学轨迹分析方法 |
| WO2023215887A1 (fr) * | 2022-05-06 | 2023-11-09 | Dyno Therapeutics, Inc. | Système et procédés de prédiction de caractéristiques de séquences biologiques |
| CN115881220B (zh) * | 2023-02-15 | 2023-06-06 | 北京深势科技有限公司 | 一种抗体结构预测的处理方法和装置 |
| CN116913395B (zh) * | 2023-09-13 | 2023-11-28 | 青岛虹竹生物科技有限公司 | 一种构建小分子肽数据库的数字化方法 |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002064734A2 (fr) * | 2000-12-19 | 2002-08-22 | Palatin Technologies, Inc. | Identification de sites de repliement specifiques a la cible dans des peptides et des proteines |
| US20060020396A1 (en) * | 2002-09-09 | 2006-01-26 | Rene Gantier | Rational directed protein evolution using two-dimensional rational mutagenesis scanning |
| US20070016380A1 (en) * | 1998-10-21 | 2007-01-18 | The University Of Queensland | Protein engineering |
| US8374828B1 (en) * | 2007-12-24 | 2013-02-12 | The University Of North Carolina At Charlotte | Computer implemented system for protein and drug target design utilizing quantified stability and flexibility relationships to control function |
| US20130090265A1 (en) | 2011-10-11 | 2013-04-11 | Biolauncher Ltd. | Systems and methods for generation of context-specific, molecular field-based amino acid substitution matrices |
| WO2016005969A1 (fr) * | 2014-07-07 | 2016-01-14 | Yeda Research And Development Co. Ltd. | Procédé de conception assistée par ordinateur de protéines |
| WO2020102603A1 (fr) * | 2018-11-14 | 2020-05-22 | Rubryc Therapeutics, Inc. | Polypeptides cd25 génétiquement modifiés et leurs utilisations |
Family Cites Families (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE60015564T2 (de) * | 1999-08-02 | 2005-12-22 | Synt:Em (S.A.) | Berechnungsmethoden zur herstellung von molekularen mimetika |
| EP1482434A3 (fr) * | 2001-08-10 | 2006-07-26 | Xencor, Inc. | Automatisation de la conception des protéines pour l'élaboration des bibliothèques de protéines |
| US20070192033A1 (en) | 2006-02-16 | 2007-08-16 | Microsoft Corporation | Molecular interaction predictors |
| US8050870B2 (en) | 2007-01-12 | 2011-11-01 | Microsoft Corporation | Identifying associations using graphical models |
| AU2011305371B2 (en) * | 2010-09-21 | 2015-05-21 | Massachusetts Institute Of Technology | Human-adapted HA polypeptides, vaccines, and influenza treatment |
| WO2014022817A2 (fr) | 2012-08-03 | 2014-02-06 | Novartis Ag | Procédés pour identifier des restes acide aminé impliqués dans une liaison macromoléculaire et leurs utilisations |
| US10155031B2 (en) * | 2012-11-28 | 2018-12-18 | Biontech Rna Pharmaceuticals Gmbh | Individualized vaccines for cancer |
| CN107921090A (zh) | 2015-04-06 | 2018-04-17 | 苏伯多曼有限责任公司 | 含有从头结合结构域的多肽及其用途 |
| US20180068054A1 (en) * | 2016-09-06 | 2018-03-08 | University Of Washington | Hyperstable Constrained Peptides and Their Design |
| EP3568782A1 (fr) | 2017-01-13 | 2019-11-20 | Massachusetts Institute Of Technology | Conception d'anticorps basée sur l'apprentissage automatique |
| US20210284695A1 (en) * | 2017-04-28 | 2021-09-16 | University Of Washington | Folded and protease-resistant polypeptides |
| MX2021007556A (es) | 2018-12-21 | 2021-09-10 | Biontech Us Inc | Método y sistemas de predicción de epítopos específicos de hla de clase ii y caracterización de células t cd4+. |
-
2020
- 2020-05-13 EP EP20815607.5A patent/EP3976083A4/fr active Pending
- 2020-05-13 JP JP2021570755A patent/JP2022535511A/ja active Pending
- 2020-05-13 CA CA3142339A patent/CA3142339A1/fr active Pending
- 2020-05-13 KR KR1020217043265A patent/KR20220041784A/ko unknown
- 2020-05-13 CA CA3142227A patent/CA3142227A1/fr active Pending
- 2020-05-13 WO PCT/US2020/032724 patent/WO2020242766A1/fr unknown
- 2020-05-13 EP EP20813167.2A patent/EP3977117A4/fr active Pending
- 2020-05-13 KR KR1020217043264A patent/KR20220039659A/ko unknown
- 2020-05-13 JP JP2021571033A patent/JP2022535769A/ja active Pending
- 2020-05-13 WO PCT/US2020/032715 patent/WO2020242765A1/fr unknown
- 2020-05-13 CN CN202080050892.XA patent/CN114585918A/zh active Pending
- 2020-05-13 CN CN202080050301.9A patent/CN114401734A/zh active Pending
- 2020-12-01 US US17/108,958 patent/US11545238B2/en active Active
-
2021
- 2021-11-29 US US17/537,215 patent/US20220081472A1/en active Pending
-
2022
- 2022-10-07 US US17/961,942 patent/US20230095685A1/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070016380A1 (en) * | 1998-10-21 | 2007-01-18 | The University Of Queensland | Protein engineering |
| WO2002064734A2 (fr) * | 2000-12-19 | 2002-08-22 | Palatin Technologies, Inc. | Identification de sites de repliement specifiques a la cible dans des peptides et des proteines |
| US20060020396A1 (en) * | 2002-09-09 | 2006-01-26 | Rene Gantier | Rational directed protein evolution using two-dimensional rational mutagenesis scanning |
| US8374828B1 (en) * | 2007-12-24 | 2013-02-12 | The University Of North Carolina At Charlotte | Computer implemented system for protein and drug target design utilizing quantified stability and flexibility relationships to control function |
| US20130090265A1 (en) | 2011-10-11 | 2013-04-11 | Biolauncher Ltd. | Systems and methods for generation of context-specific, molecular field-based amino acid substitution matrices |
| WO2016005969A1 (fr) * | 2014-07-07 | 2016-01-14 | Yeda Research And Development Co. Ltd. | Procédé de conception assistée par ordinateur de protéines |
| WO2020102603A1 (fr) * | 2018-11-14 | 2020-05-22 | Rubryc Therapeutics, Inc. | Polypeptides cd25 génétiquement modifiés et leurs utilisations |
Non-Patent Citations (1)
| Title |
|---|
| See also references of EP3977117A4 |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115512763A (zh) * | 2022-09-06 | 2022-12-23 | 北京百度网讯科技有限公司 | 多肽序列的生成方法、多肽生成模型的训练方法和装置 |
| CN115512763B (zh) * | 2022-09-06 | 2023-10-24 | 北京百度网讯科技有限公司 | 多肽序列的生成方法、多肽生成模型的训练方法和装置 |
Also Published As
| Publication number | Publication date |
|---|---|
| US11545238B2 (en) | 2023-01-03 |
| CN114585918A (zh) | 2022-06-03 |
| CA3142227A1 (fr) | 2020-12-03 |
| CA3142339A1 (fr) | 2020-12-03 |
| US20210166788A1 (en) | 2021-06-03 |
| KR20220039659A (ko) | 2022-03-29 |
| WO2020242766A1 (fr) | 2020-12-03 |
| US20220081472A1 (en) | 2022-03-17 |
| EP3976083A4 (fr) | 2023-07-12 |
| EP3977117A4 (fr) | 2023-08-16 |
| EP3976083A1 (fr) | 2022-04-06 |
| US20230095685A1 (en) | 2023-03-30 |
| CN114401734A (zh) | 2022-04-26 |
| KR20220041784A (ko) | 2022-04-01 |
| EP3977117A1 (fr) | 2022-04-06 |
| JP2022535511A (ja) | 2022-08-09 |
| JP2022535769A (ja) | 2022-08-10 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP3977117A1 (fr) | Peptides modifiés à l'échelle mésométrique et procédés de sélection | |
| CN114303201B (zh) | 使用机器学习技术生成蛋白质序列 | |
| Li et al. | OptMAVEn–a new framework for the de novo design of antibody variable region models targeting specific antigen epitopes | |
| EP3880698A1 (fr) | Polypeptides cd25 génétiquement modifiés et leurs utilisations | |
| JP2009106280A (ja) | ヒトに適合したモノクローナル抗体における使用法 | |
| EP1998807A2 (fr) | Méthodes d'humanisation d'anticorps et anticorps humanisés ainsi obtenus | |
| Woldring et al. | A gradient of sitewise diversity promotes evolutionary fitness for binder discovery in a three-helix bundle protein scaffold | |
| Kim et al. | Crystal structures of mono-and bi-specific diabodies and reduction of their structural flexibility by introduction of disulfide bridges at the Fv interface | |
| Willis et al. | Human immunoglobulin repertoire analysis guides design of vaccine priming immunogens targeting HIV V2-apex broadly neutralizing antibody precursors | |
| Noël et al. | Global analysis of VHHs framework regions with a structural alphabet | |
| Shanehsazzadeh et al. | Unlocking de novo antibody design with generative artificial intelligence | |
| JP2021151236A (ja) | 三次元構造に基づくヒト化方法 | |
| JPWO2020242765A5 (fr) | ||
| Vlachakis | Antibody Clustering and 3D Modeling for Neurodegenerative Diseases | |
| KR20210142092A (ko) | 에피토프 및 파라토프를 확인하는 방법 | |
| Rampuria et al. | Molecular insights into recognition of GUCY2C by T-cell engaging bispecific antibody anti-GUCY2CxCD3 | |
| Leem | Development of computational methodologies for antibody design | |
| VIART | Computational design of peptide ligands based on antibody-antigen interface properties |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 20813167 Country of ref document: EP Kind code of ref document: A1 |
|
| ENP | Entry into the national phase |
Ref document number: 2021570755 Country of ref document: JP Kind code of ref document: A Ref document number: 3142227 Country of ref document: CA |
|
| NENP | Non-entry into the national phase |
Ref country code: DE |
|
| ENP | Entry into the national phase |
Ref document number: 2020813167 Country of ref document: EP Effective date: 20220103 |